Neurodegenerative changes are associated with protein translation

To explore new mutations associated with neurodegenerative and cognitive deficits, researchers have found that when two mice that function in the same critical pathway lose their genes, they cause neurodegeneration. Surprisingly, both genes are involved in protein translation, one of which encodes a transporter RNA that is specifically expressed in the brain—the first gene that is differentially expressed in vertebrates.

In theory, eukaryotes need to encode approximately 42 different tRNA genes to decode 61 mRNA triplet codes, while the vertebrate genome contains hundreds of tRNA genes. So far, researchers have speculated that this redundancy exists because a large amount of tRNA is needed to satisfy the constant translation of mRNA into protein. It is also curious that mutations in this tRNA are only present in specific, widely studied experimental mice. This research July 24th Published in the journal Science, it is suggested that some tRNA genes may have tissue-specific functions rather than redundancy.

Ambro van Hoof , a molecular biologist at the University of Texas at Houston who studies mRNA degradation but is not involved in the work, said "it has always been thought that more tRNAs only produce more tRNAs , but this study strongly suggests Specific tRNA genes in animals have special functions, they are not exactly the same."

Susan Ackerman , a scientist who studies the molecular mechanism of neurodegeneratives in the Jackson Laboratory in Bar Harbor, Maine, is one of the authors of the study. He said: "We believe that tRNA biology has been thoroughly studied, but still There are many problems to solve. The central nervous system specificity of this tRNA is completely unexpected for us. I think this work declares, 'Don't ignore these genes, they are really important.'"

In a genetic screen, Ackerman and her colleagues identified an ataxia mouse whose cerebellar neuron died, retinal neurodegeneration, and died nine weeks later. But when they used these mice to hybridize with another strain of mice to map the causal aberrations, the resulting phenotype frequency was much lower than expected. Further genetic studies and cross-breeding experiments led the team to identify a modified point mutation on the arginine tRNA gene, but only in C57BL/6J (B6J) strain mice. In other mouse strains, only mutations did not result in neurodegenerative changes, suggesting that the two mutations work together.

Hoof said: "I am very excited to see that two specific defects in the normal protein translation process in these mice can cause a specific disease."

The researchers first identified a mutation in the GTPBP2 gene, which encodes a rarely studied protein that is part of the ribosome-releasing factor family and acts to reduce ribosome stall during translation. This protein is normally expressed in large amounts but varies in mutant mice. Later, these researchers found that only the GTPBP2 gene mutation combined with tRNA mutations resulted in a neurodegenerative phenotype.

Using ribosome analysis, the researchers found that it is easier to stop at one of the arginine codons when the ribosome passes the genomic information in the brain tissue of the mutant mouse. Ackerman said: "We didn't know what it meant to stop the ribosome. The researchers knew that yeast lacked one of the ribosome releasing factors and grew very slowly, but no phenotypic cues were found in higher organisms."

Jennifer Darnell , a molecular neuroscientist at Rockefeller University in New York, said: "This research with new discoveries and amazing discoveries is valuable. The authors have discovered a new ribosome releasing factor and found it with nerves. Degenerative changes in brain-specific tRNA mutations. They also emphasized the importance of protein synthesis for maintaining healthy neuronal function. They also revealed the importance of mouse strains."

Louis Levinger , a tRNA researcher at York College, New York City University, agrees. He said: "This work that combines at least four different research areas is very meaningful and has an impressive research width!"

“This changed my understanding of the protein translation process,” van Hoof added. “There was previously thought that a single ribosome releasing factor was associated with a stalled ribosome, but the question now is whether there is a specific factor and ribosome stop. Related to whether these factors have different functions."
Ackerman 's team is now working to address this and other issues, such as whether tRNA- arginine mutations are associated with other neurological phenotypes, and why neurons die when ribosomes stop. "

This study also highlights the issue of strain background in mouse genetic studies. "This is a big problem in the field of neurodegeneration," Darnell said. "Many researchers have experimented with mice from a single line and have never questioned the role of the genetic background. This is really a time for people in this field. Alarm. We need to create better guidelines for researchers so that the mouse model for human disease can be properly used."

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